Following is a synthesis for albuterol (Proventil), currently one of the most widely used inhalation bronchodilators. (a) Propose a mechanism for conversion of 4-hydroxybenzaldehyde to \(\mathrm{A}\). (b) Propose reagents and experimental conditions for conversion of \(\mathrm{A}\) to \(\mathrm{B}\). (c) Propose a mechanism for the conversion of B to \(\mathrm{C}\). Hint: Think of trimethylsulfonium iodide as producing a sulfur equivalent of a Wittig reagent. (d) Propose reagents and experimental conditions for the conversion of \(C\) to \(D\). (e) Propose reagents and experimental conditions for the conversion of D to albuterol. (f) Is albuterol chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Step by step solution

01

(a) Mechanism for conversion of 4-hydroxybenzaldehyde to A#

The conversion of 4-hydroxybenzaldehyde to A involves the formation of an imine from an aldehyde and an amine. In this reaction, the amine used is N,N-dimethylethylamine. The mechanism involves the nucleophilic attack of the amine's lone pair of electrons on the carbonyl carbon of the aldehyde followed by the elimination of water to form the imine.

02

(b) Reagents and conditions for conversion of A to B#

To convert A to B, we need to reduce the imine to an amine. A suitable reducing agent for this conversion is sodium cyanoborohydride (NaBH3CN). The experimental conditions are standard for this type of reduction: a mild acidic or neutral environment and a controlled temperature (room temp or slightly elevated).

03

(c) Mechanism for the conversion of B to C#

Trimethylsulfonium iodide acts as a sulfur equivalent of a Wittig reagent, so we can treat its mechanism similarly. The reaction involves formation of a ylide from the iodide and the phosphonium salt, followed by the nucleophilic attack of the ylide carbon on the aldehyde carbonyl, and finally the elimination of the thiophosphate byproduct to form the double bond in compound C.

04

(d) Reagents and experimental conditions for the conversion of C to D#

To convert C to D, we need to perform a halogenation and substitution to add the ethylene group. First, treat compound C with N-bromosuccinimide (NBS) in the presence of benzoyl peroxide (as a radical initiator) to introduce the bromine atom. Then perform an S_N2 substitution reaction with ethylene oxide to replace the bromine with the ethylene group to obtain compound D. Nucleophilic attack of the ethylene oxide helps to substitute bromide with the ethylene group.

05

(e) Reagents and experimental conditions for the conversion of D to albuterol#

To convert D to albuterol, we need to perform an etherification reaction. First, protect the amine group with an acetyl group by adding acetic anhydride followed by lithium aluminum hydride (LiAlH4) reduction to obtain the free alcohol. Next, perform a Williamson ether synthesis by treating the alcohol with a strong base, such as sodium hydride, to form an alkoxide, followed by reaction with para-nitrophenyl acetate to produce the protected albuterol. Finally, deprotect the amine group by reacting it with a mild base such as potassium carbonate in water.

06

(f) Chirality #

Albuterol is indeed chiral, having two chiral centers: one at the carbon bonded to the bromine in compound C, and the other at the carbon attached to the ethylene group in compound D. Thus, there are four possible stereoisomers (2^2) of albuterol. This synthesis does not control the stereochemistry in the bromination or ethylene group addition steps, so it will form a mixture of these four stereoisomers.

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